Enterodiol and Enterolactone Modulate the Immune Response by Acting on Nuclear Factor-κB (NF-κB) Signaling

Abstract

Lignan-rich whole-grain cereals, beans, berries, and nuts show protective effects against a variety of chronic diseases, including cancer. Lignans are converted by intestinal microflora to enterolactone (EL) and its oxidation product enterodiol (ED). To investigate the immunomodulatory effect of EL and ED in human cells, peripheral blood lymphocytes were treated with increasing physiologically relevant concentrations of EL and ED (0-1000 microM) and stimulated with lipopolysaccharide (LPS) and anti-CD3 plus anti-CD28 monoclonal antibodies. A dose-related inhibition of cell proliferation and cytokine production was observed, with EL being the most active. Molecular investigations in THP-1 cells showed that both EL and ED prevented inhibitory-kappaB (I-kappaB) degradation and nuclear factor-kappaB (NF-kappaB) activation, which in turn resulted in decreased tumor necrosis factor-alpha (TNF-alpha) production. EL and ED were also able to pass the intestinal barrier and modulate cytokine production. The findings of the present study reveal potential mechanisms that could explain some in vivo beneficial effects of lignans.

Role of ABCG2 in Transport of the Mammalian Lignan Enterolactone and its Secretion into Milk in Abcg2 Knockout Mice

“…These levels of bioavailable metabolites can exert modulatory effects in cells through selective actions on different components of the intracellular signaling cascades, which are vital for cellular functions such as growth, proliferation, and apoptosis (Crozier et al, 2009;Corsini et al, 2010). Therefore, the concentrations used in the present study (10 mm/l) are physiologically relevant (Corsini et al, 2010). In addition, the metabolism and tissue distribution of enterolactone as well as its enterohepatic circulation (Högger, 2013) may be directly influenced by ABCG2 interaction.…”

“…The metabolites of dietary phenolics, such as enterolignans, reach the systemic bloodstream in the range from nmol/l to low mmol/l concentrations. These levels of bioavailable metabolites can exert modulatory effects in cells through selective actions on different components of the intracellular signaling cascades, which are vital for cellular functions such as growth, proliferation, and apoptosis (Crozier et al, 2009;Corsini et al, 2010). Therefore, the concentrations used in the present study (10 mm/l) are physiologically relevant (Corsini et al, 2010).…”

“…A significant concentration of enterolactone has been reported in bovine milk (Antignac et al, 2004). In general, under normal dietary conditions, enterolactone is the enterolignan that reaches the highest concentration in plasma (Kuijsten et al, 2006;Högger, 2013) and is the most effective metabolite in the inhibition of cell proliferation (Corsini et al, 2010;Azrad et al, 2013). Owing to the potential beneficial effects of enterolactone and the complex relationship between the colonic environment and other factors contributing to systemic exposure of such compounds to ABC transporters, a study of the interaction of ABCG2 with enterolactone could be of particular relevance.…”

Flaxseed-Derived Enterolactone Is Inversely Associated with Tumor Cell Proliferation in Men with Localized Prostate Cancer

“…8 A recent investigation reported reductions in NFjB activation by enterolactone and enterodiol with decreased activation of downstream intracellular signaling targets involved in inflammation. 9 Further, it has been suggested that the transition from indolent tumor growth to more-aggressive tumor proliferation is accompanied by the onset of angiogenesis in a process coined, the angiogenic switch. 10 Thus, there is a rationale to hypothesize that therapies that inhibit angiogenesis would also exhibit anticarcinogenic properties.…”

Cloning, expression, and characterization of a four-component O-demethylase from human intestinal bacterium Eubacterium limosum ZL-II

“…Phytoestrogens are superior in causing lower side-effects when administered for the treatment of illnesses (Gonzalez-Vallinas et al 2013;Hard and Edelstein 2015;Potocka et al 2013;Sharma et al 2014). Enterodiol (END) and enterolactone (ENL) are two important lignan-type phytoestrogens, which are associated with reduced risk of acute coronary events and many chronic diseases (Corsini et al 2010;Hu et al 2007;Sirotkin and Harrath 2014;Wang 2002). According to pharmacokinetics studies, high concentrations of END and ENL can be detected in the blood circulation after oral administration of…”